Brianna Dalesandro

The d ‐peptide ^DTBP‐3 was identified, which could effectively block TIGIT/PVR interaction. ^DTBP‐3 could inhibit tumor growth and metastasis in anti‐PD‐1 resistant tumor model and could serve as a potential candidate for cancer immunotherapy.

Abstract

The low response rate and adaptive resistance of PD‐1/PD‐L1 blockade demands the studies on novel therapeutic targets for cancer immunotherapy. We discovered that a novel immune checkpoint TIGIT expressed higher than PD‐1 in many tumors especially anti‐PD‐1 resistant tumors. Here, mirror‐image phage display bio‐panning was performed using the d ‐enantiomer of TIGIT synthesized by hydrazide‐based native chemical ligation. d ‐peptide ^DTBP‐3 was identified, which could occupy the binding interface and effectively block the interaction of TIGIT with its ligand PVR. ^DTBP‐3 showed proteolytic resistance, tumor tissue penetrating ability, and significant tumor suppressing effects in a CD8⁺ T cell dependent manner. More importantly, ^DTBP‐3 could inhibit tumor growth and metastasis in anti‐PD‐1 resistant tumor model. This is the first d ‐peptide targeting TIGIT, which could serve as a potential candidate for cancer immunotherapy.

Related Articles

Multivalent antibody-recruiting macromolecules: linking increased binding affinities with enhanced innate immune killing.

Chembiochem. 2020 Jun 04;:

Authors: Uvyn A, de Geest B

Abstract
Antibody-recruiting molecules (ARMs) are a novel class of immunotherapeutics. They are capable of introducing antibodies on disease-relevant targets such as cancer cells, bacterial cells or viruses. This can induce antibody-mediated immune responses such as antibody dependent cellular cytotoxicity (ADCC), complement dependent cytotoxicity (CDC) and phagocytosis which can lead to killing of the pathogen. In contrast to the classic ARMs, multivalent antibody-recruiting macromolecules could offer an advantage in view of increasing the efficiency of antibody recruitment and subsequent innate immune killing. Such compounds consist of multiple target binding termini (TBT) and/or antibody binding termini (ABT). Those multivalent interactions are able to convert low binding affinities into increased binding avidities. This review summarizes the current status on multivalent antibody-recruiting macromolecules and gives insight into possible benefits, still to overcome hurdles and future perspectives.

PMID: 32497371 [PubMed - as supplied by publisher]

Chemical-induced spores of the Gram-negative bacterium Myxococcus xanthus are peptidoglycan (PG)-deficient. It is unclear how these spherical spores germinate into rod-shaped, walled cells without preexisting PG templates. We found that germinating spores first synthesize PG randomly on spherical surfaces. MglB, a GTPase-activating protein, forms a cluster that responds to the...

Related Articles

How the assembly and protection of the bacterial cell envelope depend on cysteine residues.

J Biol Chem. 2020 06 02;:

Authors: Collet JF, Cho SH, Iorga BI, Goemans CV

Abstract
The cell envelope of Gram-negative bacteria is a multilayered structure essential for bacterial viability; the peptidoglycan cell wall provides shape and osmotic protection to the cell, and the outer membrane serves as a permeability barrier against noxious compounds in the external environment. Assembling the envelope properly and maintaining its integrity is a matter of life and death for bacteria. Our understanding of the mechanisms of envelope assembly and maintenance has increased tremendously over the last two decades. Here, we review the major achievements during this time, giving central stage to the amino acid cysteine, one of the least abundant amino acid residues in proteins, whose unique chemical and physical properties often critically support biological processes. First, we review how cysteines contribute to envelope homeostasis by forming stabilizing disulfides in crucial bacterial assembly factors (LptD, BamA, and FtsN) and stress sensors (RcsF and NlpE). Second, we highlight the emerging role of enzymes that use cysteine residues to catalyze reactions that are necessary for proper envelope assembly, and we also explain how these enzymes are protected from oxidative inactivation. Finally, we suggest future areas of investigation, including a discussion of how cysteine residues could contribute to envelope homeostasis by functioning as redox switches. By highlighting the redox pathways that are active in the envelope of Escherichia coli, we provide a timely overview on the assembly of a cellular compartment that is the hallmark of Gram-negative bacteria.

PMID: 32487747 [PubMed - as supplied by publisher]

Related Articles

Bacterial Cell Mechanics Beyond Peptidoglycan.

Trends Microbiol. 2020 May 25;:

Authors: Mathelié-Guinlet M, Asmar AT, Collet JF, Dufrêne YF

Abstract
The bacterial cell envelope plays essential roles in controlling cell shape, division, pathogenicity, and resistance against external stresses. In Escherichia coli, peptidoglycan (PG) has long been thought to be the primary component that conveys mechanical strength to the envelope. But a recent publication demonstrates the key contribution of the lipoprotein Lpp in defining the stiffness of the cell envelope and its sensitivity to drugs.

PMID: 32466989 [PubMed - as supplied by publisher]

Related Articles

Interactions of probiotics and prebiotics with the gut microbiota.

Prog Mol Biol Transl Sci. 2020;171:265-300

Authors: Ballan R, Battistini C, Xavier-Santos D, Saad SMI

Abstract
The gut microbiota (GM) composition varies among individuals and is influenced by intrinsic (genetics, age) and extrinsic (environment, diet, lifestyle) factors. An imbalance or dysbiosis is directly associated with the development of several illnesses, due to the potential increase in intestinal permeability leading to a systemic inflammation triggered by higher levels of circulating lipopolysaccharides and changes in the immune response caused by an overgrowth of a specific genus or of pathogens. These mechanisms may increase symptoms in gastrointestinal disorders or reduce glucose tolerance in metabolic diseases. Diet also has a significant impact on GM, and functional foods, namely prebiotics and probiotics, are a novel approach to reestablish the indigenous microbiota. Prebiotics, like inulin and polyphenols, are selectively utilized by GM, releasing short-chain fatty acids (SCFA) and other metabolites which may reduce the intestinal lumen pH, inhibit growth of pathogens, and enhance mineral and vitamin bioavailability. Probiotic microorganism may increase the microbial diversity of GM and improve the integrity of the intestinal barrier, leading to an improvement of baseline and pathologic inflammation. In this chapter, we will discuss the potential roles of prebiotics and probiotics in health and diseases throughout an individual's lifetime and proposed mechanisms of action.

PMID: 32475525 [PubMed - in process]

Related Articles

In Silico Design and Evaluation of Acinetobacter baumannii Outer Membrane Protein a Antigenic Peptides As Vaccine Candidate in Immunized Mice.

Iran J Allergy Asthma Immunol. 2019 Nov 10;18(6):655-663

Authors: Mehdinejadiani K, Bandehpour M, Hashemi A, Ranjbar MM, Taheri S, Jalali SA, Mosaffa N

Abstract
Acinetobacter baumannii is a Gram-negative bacterium that has recently been identified as a leading nosocomial pathogen. Infections by this pathogen result in significant mortality due to antibiotic resistance. An effective vaccine would help alleviate the burden of disease incurred by this pathogen; however, there are currently no licensed vaccines offering protection against Acinetobacter baumannii infection. In this study, considering the fact that outer membrane protein A is one of the most promising vaccine candidates, we predicted T cell and B cell epitopes on this protein using sequence-based epitope prediction tools and determined whether or not mice immunized with these peptides induce an immune response. We selected consensus epitopes including five peptides in different tools with the highest score. 48 female C5BL/6 SPF injected subcutaneously with the peptides (peptide1 to peptide 5 separately) in 100 μL of the solution and sham groups received adjuvant and PBS alone on the same schedule: on day 0 (primary dose) and two booster doses were administered on days 14 and 28. At the end of time, animals euthanized by Isoflurane, and collected sera for assessment of specific antibodies against each peptide by ELISA (Enzyme-linked immunosorbent assay). Immunization of mice showed one of the novel synthetic peptides (peptide 1 (24-50 amino acids)) elicited immune responses. We conclude to combine theoretical methods of epitope prediction and evaluating the potential of immunogenicity for developing vaccines is important.

PMID: 32245309 [PubMed - indexed for MEDLINE]

Peptide synthesis goes green : A water‐compatible 2,7‐disulfo‐9‐fluorenylmethoxycarbonyl (Smoc) protecting group has been developed that enables solid‐phase peptide synthesis under aqueous conditions as well as efficient postsynthetic purification of the peptides. This protecting group is fluorescent both when attached to an N_α atom and when cleaved and so also allows real‐time monitoring of building block coupling.

Abstract

The growing interest in synthetic peptides has prompted the development of viable methods for their sustainable production. Currently, large amounts of toxic solvents are required for peptide assembly from protected building blocks, and switching to water as a reaction medium remains a major hurdle in peptide chemistry. We report an aqueous solid‐phase peptide synthesis strategy that is based on a water‐compatible 2,7‐disulfo‐9‐fluorenylmethoxycarbonyl (Smoc) protecting group. This approach enables peptide assembly under aqueous conditions, real‐time monitoring of building block coupling, and efficient postsynthetic purification. The procedure for the synthesis of all natural and several non‐natural Smoc‐protected amino acids is described, as well as the assembly of 22 peptide sequences and the fundamental issues of SPPS, including the protecting group strategy, coupling and cleavage efficiency, stability under aqueous conditions, and crucial side reactions.

Related Articles

Macrophage-driven nutrient delivery to phagosomal Staphylococcus aureus supports bacterial growth.

EMBO Rep. 2020 May 25;:e50348

Authors: Flannagan RS, Heinrichs DE

Abstract
Staphylococcus aureus is a notorious pathogen causing significant morbidity and mortality worldwide. The ability of S. aureus to survive and replicate within phagocytes such as macrophages represents an important facet of immune evasion and contributes to pathogenesis. The mechanisms by which S. aureus acquires nutrients within host cells to support growth remain poorly characterized. Here, we demonstrate that macrophages infected with S. aureus maintain their dynamic ruffling behavior and consume macromolecules from the extracellular milieu. To support the notion that fluid-phase uptake by macrophages can provide S. aureus with nutrients, we utilized the pharmacological inhibitors PIK-III and Dynasore to impair uptake of extracellular macromolecules. Inhibitor treatment also impaired S. aureus replication within macrophages. Finally, using a mutant of S. aureus that is defective in purine biosynthesis we show that intracellular growth is inhibited unless the macrophage culture medium is supplemented with the metabolite inosine monophosphate. This growth rescue can be impaired by inhibition of fluid-phase uptake. In summary, through consumption of the extracellular environment macrophages deliver nutrients to phagolysosomal S. aureus to promote bacterial growth.

PMID: 32452129 [PubMed - as supplied by publisher]

Nature Reviews Microbiology, Published online: 26 May 2020; doi:10.1038/s41579-020-0367-2

In this Review, Ruff, Greiling and Kriegel discuss the mechanisms through which the microbiota contributes to the predisposition, initiation and perpetuation of immune-mediated diseases, and explore the therapeutic avenues that either target the microbiota, the barrier surfaces or the host immune system to restore tolerance and homeostasis.

Enhanced cytotoxicity against solid tumors by bispecific antibody-armed CD19 CAR T cells: a proof-of-concept study.

J Cancer Res Clin Oncol. 2020 May 24;:

Authors: Thakur A, Scholler J, Schalk DL, June CH, Lum LG

Abstract
PURPOSE: Although adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells has shown durable clinical efficacy in patients with CD19+ B cell malignancies, the application of this approach to solid tumors is challenging. The goal of this proof-of-concept study was to investigate whether loading of CD19-CAR T cells (CART19) with anti-HER2 or anti-EGFR bispecific antibodies (BiAb) will target HER2+/EGFR+ CD19- targets and signal the intracellular domain of CAR without engaging antigen-specific CD19 ScFv of CAR T cells.
METHODS: We used CART19 armed with anti-CD3 (OKT3) × anti-HER2 BiAb (HER2Bi) or anti-CD3 (OKT3) × anti-EGFR BiAb (EGFRBi) to evaluate the cytotoxicity directed at HER2 or EGFR expressing cancer cell lines compared with unarmed CART19 measured by short-term 51Cr release assay and long-term real-time cell analysis using xCelligence. We also determined the differences in exhaustion or effector phenotypes and cytokine profiles during the short- and long-term cytotoxicity assays.
RESULTS: Specific cytotoxicity was exhibited by CART19 armed with HER2Bi or EGFRBi against multiple tumor cell lines. Armed CART19 and armed activated T cells (ATC) showed comparable specific cytotoxicity that ranged between 10 and 90% against breast, pancreatic, ovarian, prostate, and lung cancer cell lines at 10:1 E/T ratio. Serial killing (repeated killing) by HER2Bi-armed CART19 ranged between 80 and 100% at 10:1 E/T ratio against MCF-7 cells up to 19 days (up to 4th round of repeated killing) measured by a real-time cell analysis without CART19 becoming exhausted.
CONCLUSIONS: HER2Bi- or EGFRBi-armed CART19 exhibited specific cytotoxicity against multiple HER2+/EGFR+/CD19- tumor targets in overnight and long-term serial killing assays. CART19 showed improved survival and were resistant to exhaustion after prolonged repeated exposure to tumor cells.

PMID: 32449004 [PubMed - as supplied by publisher]

Roles of LysM and LytM domains in resuscitation-promoting factor (Rpf) activity and Rpf-mediated peptidoglycan cleavage and dormant spore reactivation.

J Biol Chem. 2020 May 20;:

Authors: Sexton DL, Herlihey FA, Brott AS, Crisante DA, Shepherdson E, Clarke AJ, Elliot MA

Abstract
Bacterial dormancy can take many forms, including formation of Bacillus endospores, Streptomyces exospores, and metabolically latent Mycobacterium cells. In the actinobacteria, including the streptomycetes and mycobacteria, the rapid resuscitation from a dormant state requires the activities of a family of cell-wall lytic enzymes called resuscitation-promoting factors (Rpfs). Whether Rpf activity promotes resuscitation by generating peptidoglycan fragments (muropeptides) that function as signaling molecules for spore germination or by simply remodeling the dormant cell wall has been the subject of much debate. Here, to address this question, we used mutagenesis and peptidoglycan binding and cleavage assays to first gain broader insight into the biochemical function of diverse Rpf enzymes. We show that their LysM and LytM domains enhance Rpf enzyme activity; their LytM domain and, in some cases their LysM domain, also promoted peptidoglycan binding. We further demonstrate that the Rpfs function as endo-acting lytic transglycosylases, cleaving within the peptidoglycan backbone.  We also found that unlike in other systems, Rpf activity in the streptomycetes is not correlated with peptidoglycan-responsive Ser/Thr kinases for cell signaling, and the germination of rpf mutant strains could not be stimulated by the addition of known germinants. Collectively, these results suggest that in Streptomyces, Rpfs have a structural rather than signaling function during spore germination, and that in the actinobacteria, any signaling function associated with spore resuscitation requires the activity of additional yet to be identified enzymes.

PMID: 32434927 [PubMed - as supplied by publisher]

Nature Communications, Published online: 25 May 2020; doi:10.1038/s41467-020-16124-9

Ultrasensitive methods for detection of biomarkers for infectious disease are needed for diagnosing, monitoring and targeting treatment. Here the authors develop a digital assay for inflammatory markers, bacterial DNA and antibotic-resistance genes and apply it to characterise asthma patients and predict mortality from septic shock.

Engineering chimeric antigen receptor-natural killer cells for cancer immunotherapy.

Immunotherapy. 2020 May 21;:

Authors: Zhao Y, Zhou X

Abstract
Adoptive cell transfer has attracted considerable attention as a treatment for cancer. The success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for the treatment of haematologic tumors has demonstrated the potential of CAR. In this review, we describe the current CAR-engineered natural killer (CAR-NK) cell construction strategies, including the design principles and structural characteristics of the extracellular, transmembrane and intracellular regions of the CAR structure. In addition, we review different cellular carriers used to develop CAR-NK cells, highlighting existing problems and challenges. We further discuss possible ways to optimize CAR from the perspective of the tumor microenvironment to harness the strength of CAR-NK cells and provided rationales to combine CAR-NK cells with other treatment regimens to enhance antitumor effects.

PMID: 32436428 [PubMed - as supplied by publisher]

Recent Developments in the Application of Flow Cytometry to Advance our Understanding of Mycobacterium tuberculosis Physiology and Pathogenesis.

Cytometry A. 2020 May 21;:

Authors: Parbhoo T, Sampson SL, Mouton JM

Abstract
The ability of the bacterial pathogen Mycobacterium tuberculosis to adapt and survive within human cells to disseminate to other individuals and cause active disease is poorly understood. Research supports that as M. tuberculosis adapts to stressors encountered in the host, it exhibits variable physiological and metabolic states that are time and niche-dependent. Challenges associated with effective treatment and eradication of tuberculosis (TB) are in part attributed to our lack of understanding of these different mycobacterial phenotypes. This is mainly due to a lack of suitable tools to effectively identify/detect heterogeneous bacterial populations, which may include small, difficult-to-culture subpopulations. Importantly, flow cytometry allows rapid and affordable multiparametric measurements of physical and chemical characteristics of single cells, without the need to preculture cells. Here, we summarize current knowledge of flow cytometry applications that have advanced our understanding of the physiology of M. tuberculosis during TB disease. Specifically, we review how host-associated stressors influence bacterial characteristics such as metabolic activity, membrane potential, redox status and the mycobacterial cell wall. Further, we highlight that flow cytometry offers unprecedented opportunities for insight into bacterial population heterogeneity, which is increasingly appreciated as an important determinant of disease outcome. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

PMID: 32437069 [PubMed - as supplied by publisher]

Cationic Peptidopolysaccharide with an Intrinsic AIE Effect for Combating Bacteria and Multicolor Imaging.

Adv Healthc Mater. 2020 May 19;:e2000419

Authors: Dong Z, Wang Y, Wang C, Meng H, Li Y, Wang C

Abstract
An antibacterial polymer peptidopolysaccharide (COS-AMP) that integrates antibacterial and detection functions is constructed with a simple synthetic method. The COS-AMP is constructed by simulating the structure of peptidoglycan of the bacterial cell wall with chitooligosaccharide with intrinsic aggregation-induced emission (AIE) effect as the main chain, as well as a peptide polymer grafted onto its amino group. Based on the AIE effect and excitation-dependent fluorescence of COS-AMP, it is tentatively applied to multicolor imaging and quantification of bacteria. This multicolor imaging helps to match different excitation sources of fluorescent instrument for straightforward imaging and detection. The structural similarity with the bacterial cell wall component facilitates the passage of COS-AMP across the cell wall and destroys the bacterial structure, thus it has a good broad-spectrum antibacterial activity. In addition, aromatic fluorophores are not needed, and excellent biocompatibility will make it have broad application prospects.

PMID: 32431089 [PubMed - as supplied by publisher]

Small molecule sensors targeting the bacterial cell wall.

ACS Infect Dis. 2020 May 20;:

Authors: Parker MFL, Flavell RR, Luu J, Rosenberg OS, Ohliger MA, Wilson DM

Abstract
This review highlights recent efforts to detect bacteria, using engineered small molecules that are processed and incorporated similarly to their natural counterparts. There are both scientific and clinical justifications for these endeavors. The use of detectable, cell-wall targeted chemical probes has elucidated microbial behavior, with several fluorescent labeling methods in widespread laboratory use. Furthermore, many existing efforts including ours, focus on developing new imaging tools to study infection in clinical practice. The bacterial cell wall, a remarkably rich and complex structure, is an outstanding target for bacteria-specific detection. Several cell wall components are found in bacteria but not mammals, especially peptidoglycan, lipopolysaccharide, and teichoic acids. As this review highlights, the development of laboratory tools for fluorescence microscopy has vastly outstripped related positron emission tomography (PET) or single photon emission computed tomography (SPECT) radiotracer development. However, there is great synergy between these chemical strategies which both employ mimicry of endogenous substrates to incorporate detectable structures. As the field of bacteria-specific imaging grows, it will be important to understand the mechanisms involved in microbial incorporation of radionuclides. Additionally, we will highlight the clinical challenges motivating this imaging effort.

PMID: 32433879 [PubMed - as supplied by publisher]

Activity of mammalian peptidoglycan-targeting immunity against Pseudomonas aeruginosa.

J Med Microbiol. 2020 Apr;69(4):492-504

Authors: Torrens G, Escobar-Salom M, Oliver A, Juan C

Abstract
Pseudomonas aeruginosa is one of the most important opportunistic pathogens, whose clinical relevance is not only due to the high morbidity/mortality of the infections caused, but also to its striking capacity for antibiotic resistance development. In the current scenario of a shortage of effective antipseudomonal drugs, it is essential to have thorough knowledge of the pathogen's biology from all sides, so as to find weak points for drug development. Obviously, one of these points could be the peptidoglycan, given its essential role for cell viability. Meanwhile, immune weapons targeting this structure could constitute an excellent model to be taken advantage of in order to design new therapeutic strategies. In this context, this review gathers all the information regarding the activity of mammalian peptidoglycan-targeting innate immunity (namely lysozyme and peptidoglycan recognition proteins), specifically against P. aeruginosa. All the published studies were considered, from both in vitro and in vivo fields, including works that envisage these weapons as options not only to potentiate their innate effects within the host or for use as exogenously administered treatments, but also harnessing their inflammatory and immune regulatory capacity to finally reduce damage in the patient. Altogether, this review has the objective of anticipating and discussing whether these innate immune resources, in combination or not with other drugs attacking certain P. aeruginosa targets leading to its increased sensitization, could be valid therapeutic antipseudomonal allies.

PMID: 32427563 [PubMed - in process]

Related Articles

Utility of bacterial peptidoglycan recycling enzymes in the chemoenzymatic synthesis of valuable UDP sugar substrates.

Methods Enzymol. 2020;638:1-26

Authors: Ukaegbu OI, DeMeester KE, Liang H, Brown AR, Jones ZS, Grimes CL

Abstract
Uridine diphosphate (UDP) sugars are essential precursors for glycosylation reactions in all forms of life. Reactions that transfer the carbohydrate from the UDP donor are catalyzed by glycosyltransferases (Gtfs). While the stereochemistry and negative physiological charge of UDP-sugars are essential for their biochemical function in the cell, these characteristics make them challenging molecules to synthesize and purify on scale in the laboratory. This chapter focuses on the utilization of a chemoenzymatic synthesis of muramyl UDP-sugars, key building blocks in the bacterial cell peptidoglycan. A scalable strategy to obtain UDP-N-acetyl muramic acid derivatives (UDP-NAM), the first committed intermediate used solely in peptidoglycan biosynthesis, is described herein. This methodology utilizes two enzymes involving the cell wall recycling enzymes MurNAc/GlcNAc anomeric kinase (AmgK) and NAM α-1-phosphate uridylyl transferase (MurU), respectively. The promiscuity of these enzymes allows for the unique chemical functionality to be embedded in bacterial peptidoglycan both in vitro and in whole bacterial cells for subsequent structural and functional studies of this important biopolymer.

PMID: 32416908 [PubMed - as supplied by publisher]

Nature Reviews Microbiology, Published online: 18 May 2020; doi:10.1038/s41579-020-0366-3

In this Review Egan, Errington and Vollmer discuss new insights into the molecular mechanisms of peptidoglycan synthesis, sacculus growth regulation and bacterial morphology, as well as how bacteria achieve robust cell wall growth under different conditions and stresses.

Nature Communications, Published online: 20 May 2020; doi:10.1038/s41467-020-16505-0

There is currently no licensed SARS-CoV-2 vaccine. Here, the authors generate an optimized DNA vaccine candidate encoding the SARS-CoV-2 spike antigen, demonstrating induction of specific T cells and neutralizing antibody responses in mice and guinea pigs. These initial results support further development of this vaccine candidate.

Surface Modifications for Improved Delivery and Function of Therapeutic Bacteria.

Small. 2020 May 14;:e2001705

Authors: Vargason AM, Santhosh S, Anselmo AC

Abstract
Live therapeutic bacteria (LTBs) hold promise to treat microbiome-related diseases. However, few approaches to improve the colonization of LTBs in the gastrointestinal tract exist, despite colonization being a prerequisite for efficacy of many LTBs. Here, a modular platform to rapidly modify the surface of LTBs to enable receptor-specific interactions with target surfaces is reported. Inspired by bacterial adhesins that facilitate colonization, synthetic adhesins (SAs) are developed for LTBs in the form of antibodies conjugated to their surface. The SA platform is nontoxic, does not alter LTB growth kinetics, and can be used with any antibody or bacterial strain combination. By improving adhesion, SA-modified bacteria demonstrate enhanced in vitro pathogen exclusion from cell monolayers. In vivo kinetics of SA-modified LTBs is tracked in the feces and intestines of treated mice, demonstrating that SA-modified bacteria alter short-term intestinal transit and improve LTB colonization and pharmacokinetics. This platform enables rapid formation of an intestinal niche, leading to an increased maximum concentration and a 20% improvement in total LTB exposure. This work is the first application of traditional pharmacokinetic analysis to design and evaluate LTB drug delivery systems and provides a platform toward controlling adhesion, colonization, and efficacy of LTBs.

PMID: 32410314 [PubMed - as supplied by publisher]

Related Articles

Salmonella-Driven Polarization of Granuloma Macrophages Antagonizes TNF-Mediated Pathogen Restriction during Persistent Infection.

Cell Host Microbe. 2020 01 08;27(1):54-67.e5

Authors: Pham THM, Brewer SM, Thurston T, Massis LM, Honeycutt J, Lugo K, Jacobson AR, Vilches-Moure JG, Hamblin M, Helaine S, Monack DM

Abstract
Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium (STm) infection. We show that STm persists within splenic granulomas that are densely populated by CD11b+CD11c+Ly6C+ macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting STm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection.

PMID: 31883922 [PubMed - indexed for MEDLINE]

Related Articles

An aptamer-T cell targeted therapy for tumor treatment using sugar metabolism and click chemistry.

ACS Chem Biol. 2020 May 13;:

Authors: Liu CG, Wang Y, Liu P, Yao QL, Zhou YY, Li CF, Zhao Q, Liu GH, Zhang XL

Abstract
The development of a tumor-targeted immunotherapy is highly required. The most advanced application is the use of CD19 chimeric antigen receptor (CAR) T (CAR-T) cells to B-cell malignancies, but there are still side effects including potential carcinogenicity of lentiviral or retroviral insertion into the host cell genome. Here we developed a non-viral aptamer-T-cell targeted strategy for tumor therapy. Tumor cells surface-specific ssDNA aptamers were conjugated to CD3+T cells (aptamer-T cells) using N-azidomannosamine (ManNAz) sugar metabolic cell labeling and click chemistry. We found that the aptamer-T cells could specifically target and bind to tumor cells (such as SGC-7901 gastric cancer cell and CT26 colon carcinoma cell) in vitro and in mice after adoptively transfer in. Aptamer-T cells led to significant regression in tumor volume due to being enriched at tumor microenvironment and producing strong cytotoxicity activities of CD3+T cells with enhanced perforin, granzyme B, CD107a, CD69 and FasL expression. Moreover, aptamer-T displayed even stronger anti-tumor effects than an anti-PD1 immune-checkpoint monoclonal antibody (mAb) treatment in mice and combination with anti-PD1 yielded synergic anti-tumor effects. This study uncovers the strong potential of the adoptive non-viral aptamer-T cell strategy as a feasible and efficacious approach for tumor-targeted immunotherapy application.

PMID: 32401486 [PubMed - as supplied by publisher]